The present invention is direction to the treatment of acne and other inflammatory conditions. More specifically, in some embodiments this invention relates to methods for treating acne which methods comprise the topical application of muscarinic agents such as neostigmine. Treatment in accordance with the present invention results in improved healing in the treated area.
Acne is one example of inflammatory conditions which may be treated in accordance with the present invention.
Acne is a multi factorial disease affecting the sebaceous follicle and characterized by papules, pustules, and scars. Acne affects nearly 90% of 16-year old boys and girls but is clearly no longer a problem confined to teenagers. Recently for this condition, referral for specialists' opinions have significantly increased among people over the age of 20. It has been realized that simple attention to hygiene is no longer sufficient, and antiseptic washes so popular some years ago are now perceived as ineffective by many sufferers and most clinicians.
During puberty, elevated androgen levels stimulate the sebaceous glands to enlarge and produce increased amounts of sebum in the sebaceous follicle. Subsequent abnormal keratinization with hyperkeratosis of the follicular epithelium leads to obstruction of the duct by horny plaque. The blocked duct becomes clogged with a dense material composed of sebum and keratinous debris forming a micro comedo, a precursor of the acne lesion. The excess sebum in the micro comedo also provides an anaerobic growth medium for Propionibacterium acnes. Lipase from the bacteria hydrolyzes sebum triglycerides into free fatty acids that are both comedogenic and proinflammatory. Propionibacterium acnes also secretes chemotactic factors that attract neutrophils. Lysosomal enzyme released from the neutrophils rupture the follicle wall releasing proinflammatory mediators including keratin and lipids into the surrounding dermis. Inflammatory papules appear as a result. Further inflammation with macrophages and foreign body reactions lead to cysts and nodules. The key features of the pathogenesis of acne can be characterized as 1) increased sebum production, 2) follicular corynekeratinization, 3) bacterial proliferation, and 4) inflammation.
Effective management of acne can be accomplished by addressing the four key features of the pathogenesis. Topical therapy is usually the first choice for patients with mild-to-moderate inflammatory acne. The use of topical therapy minimizes potential side effects associated with the use of systemic agents. Topical therapies include benzoyl peroxide, which is the most commonly used non-prescription acne medication. It is an important antibacterial oxidizing agent that can decrease the number of Propionibacterium acnes and frequently the amount of free fatty acids. Benzoyl peroxide is the first line of monotherapy for mild acne and it is available in over-the-counter preparations. Benzoyl peroxide is applied once or twice daily and patients often experience mild redness and scaling of the skin during the first week of usage.
Tretinoin is the most effective topical comedolytic agent, decreasing the cohesiveness of follicular epithelial cells, and thereby inhibiting the formation of microcomedones and increasing cell turnover resulting in expulsion of existing comedones. This agent also decreases the thickness of the stratum corneum and potentiates the penetration of topical antibiotic agents. Tretinoin therapy comprises once daily application. Mild redness and peeling are a part of the therapeutic effect of the medication but can result in reduced patient compliance. Patients should be made aware that improvement may take as long as 6 to 12 weeks, and that flare-ups of acne can occur during the first few weeks of therapy. In addition, it is extremely important that patients avoid excessive exposure to the sun during treatment.
Mild inflammatory acne lesions can also be treated with topical antibiotics including erythromycin ointment, clindamycin solution, and meclocycline cream. The primary action of the antibiotics is to reduce the population of Propionibacterium acnes in the sebaceous follicle and thereby suppress the free fatty acid production. The effectiveness of topical antibiotics in the treatment of acne is limited by their low lipid solubility and subsequent difficulty in penetrating sebum-filled follicles. Topical antibiotics are applied twice daily.
Patients with moderate to severe inflammatory acne often require oral antibiotics in addition to topical therapy. The most commonly prescribed agents include tetracycline, erythromycin, minocycline, and doxycycline. Treatment is usually maintained for several months. Side effects include the overgrowth of nonsusceptible organisms including Candida, which can produce vaginal and oral yeast infections.
Patients with severe inflammatory acne unresponsive to other therapy may require treatment with oral isotretinoin. Isotretinoin is a compound related to vitamin A, and is the only agent that decreases sebum production and reverses the abnormal epithelial formation process. This agent can also decrease the population of Propionibacterium acnes in the sebaceous follicle. Duration of therapy is usually 20 weeks, and the satisfactory response rate is quite high. Treatment is often accompanied by many side effects, however, including dry skin, pruritus, epistaxis, and photosensitivity, as well as hypertriglyceridemia, abnormal liver function tests, electrolyte imbalances, and elevated platelet counts. Most serious though, is the teratogenic effect of isotretinoin. Use of isotretinoin during pregnancy is absolutely contraindicated. So serious is the potential for death or teratogenic effects to a fetus, isotretinoin is practically contraindicated in women of child-bearing age. Use of isotretinoin must be accompanied by a guarantee by the patient that conception will be avoided at any and all costs.
Because acne is a multi factorial disease which is manifest to varying degrees, it is important for the physician to assess the patient to attempt to find therapies which will be helpful to the patient without causing major side effects. All of the current conventional treatments are associated with some degree of adverse side effects that limit their usefulness. Consequently, there is a need for a drug that eliminates acne without side effects.
As discussed above, the formation of acne is frequently associated with inflammation. During the inflammatory process, white blood cells are attracted to the area of the lesion, and play a crucial role in fighting the infection. Other local infections are characterized by similar inflammatory processes. In addition, burns also trigger the body's inflammatory response.
Peripheral Analgesia Using Opioid Agents
In the past, administration of opioids has been directed at targeting opioid receptors in the central nervous system (CNS). In addition to their presence in the CNS, opioid receptors have been found on sensory nerves in inflamed subcutaneous tissue. This finding was reported in Stein et al., "Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat," Neurosci Lett, 84:225-228 (1988), and in Stein et al., "Antinociceptive effects of mu- and kappa-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism of action," Eur. J. Pharmacol., 155:255-264 (1988). Small doses of opioids, when applied locally or topically in inflamed areas outside of the central nervous system, can produce local analgesic effects by interacting with the opioid receptors on peripheral sensory nerves and producing local analgesia. This finding was discussed in Stein et al., "Opioids as novel intra-articular agents in arthritis," In: Progress in Pain Research and Management, Fields, H. L., and Liebeskind, J. C., eds., 1:289-296, IASP Press, Seattle (1994). A practical application of this phenomena is presented in U.S. Pat. No. 5,589,480 to ElKhoury et al., wherein the topical application of an opioid analgesic agent to alleviate pain is disclosed. Reference is also made to the present inventor's copending U.S. patent applications Ser. Nos. 08/741,743, 08/732,594, 09/028,117, 09/083,431, and 08/874,254, which are hereby incorporated by reference as though set forth in full herein.
Peripheral opioid effects are not initially apparent in normal tissue, but do become apparent within minutes to hours at the site of inflammation. It is believed that the reason for the pain relief is that opioids can gain easier access to neuronal opioid receptors during inflammation as a result of the disruption of the perineurium (which is normally an impermeable sheath encasing the peripheral nerve fiber). Further, the number of peripheral sensory nerve terminals is increased in inflamed tissue and a phenomenon known as sprouting occurs in which the number of fibers increases significantly within inflamed tissued. The sprouting results in a subsequent increase in the number of morphine receptors that are peripherally accessible to locally-applied opioids.
In addition to their presence in the peripheral nervous system, opioid receptors have been identified in the immune system as well. Specific opioid receptors, identified as .mu..sub.3 receptors, have been identified on white blood cells, including macrophages and peripheral blood granulocyites, both of which are involved in the immune response in humans. In addition, it has been shown that some lymphocytes, as well as some monocytes and macrophages, produce endogenous opioid peptides. These findings have led some researchers to suggest a neural-immune link. However, the manner in which these two systems interact is still quite unclear. A review of opioid receptors in immunocytes and neurons is presented in Advances in Neuroimmunology Vol. 4, pgs. 69-82 (1994), the entire content of which is hereby incorporated by reference as though set forth in full herein. The role of immune processes in peripheral opioid analgesia is presented in Chapter 27 of The Brain Immune Axis and Substance Abuse (Sharp, B. et al., eds.) (Plenum Press, New York, 1995), the entire content of which is hereby incorporated by reference as though set forth in full herein.
Unfortunately, morphine and other opioid drugs have a number of severe side effects which hamper their wide spread use and acceptance by both physicians and patients. These side effects include: addiction, nausea, inhibition of breathing, somnolence and dysphoria, all of which are mediated by morphine's action within the brain. It is still the current belief that narcotics ingested or injected will cross to the blood stream and from there go to the brain where there are morphine receptors. At that time, the narcotics are believed to attach to these morphine receptors and create a dullness of the pain but with all of the side effects described above. Of course, the worst potential effect is the addiction that can occur if the morphine is used beyond a few days or weeks on a continuous basis.
Because of the fear of addiction, the use of morphine as an analgesic has been restricted. In addition, major research efforts have been directed toward the development of morphine-like drugs that act within the brain but are devoid of the side effects. The market for these other drugs has never fully materialized because these drugs were not perceived as having the same analgesic properties of morphine and because typically these drugs were not produced to be both available in oral and injectable formats.
In the past ten years, the intraspinal method of treating pain has been extensively developed but, as more extensive use was made of this technique, a number of serious problems developed. The first problem is that the intraspinal method of treatment requires a spinal tap which of course necessitates the use of a needle to the spinal cord. The second problem results from the first in that if it is necessary to use the intraspinal method over a period of time, such as two or three weeks, medication must be injected into the spine for this period of time and the continuous needle sticks into the spine has potential hazards. Further, if it is necessary to use the intraspinal method over time, even though the dosage is substantially less compared to oral or intravenous dosages, there is still a high potential for addiction and with such addiction the resultant problems of withdrawal and its associated side effects.
Although intraspinal application of narcotics is still used to alleviate pain after surgery, this technique has the limitations with the potential for addiction as described above. In addition, it has been determined that with frail patients there is the risk that the patient can stop breathing and there have been a number of cases of respiratory arrest after the administration of narcotics using the intraspinal technique. Further, the intraspinal technique of administering narcotics creates difficulty with male patients and especially with elderly male patients in that there can be problems with urination and with consequent problems of urine retention. Finally, this intraspinal technique produces a significant itching problem as a side effect.
In recent studies, it was discovered that opioid receptors may also be located in other peripheral tissues. This was reported in Stein, C. et al., Peripheral effect of fentanyl upon nociception in inflamed tissue of the rat. Neurosci. Lett. 84:225-228 (1988), and in Stein, C. et al., Antinociceptive effects of mu- and kappa-agonists in inflammation are enhanced by a peripheral opioid receptor-specific mechanism of action. Eur. J. Pharmacol. 155:255-264 (1988). Subsequently, animal experiments were performed in Dr. Stein's laboratory characterizing peripheral opioid receptors and their activation by morphine and other opioid drugs. Stein, C., et al., N. Engl. J. Med. 325:1123-1126 (1991) also reported the analgesic effect of intraarticular morphine after arthroscopic knee surgery. These results were reviewed in Stein, C., Peripheral mechanisms of opioid analgesia. Anesth. Analg. 76:182-191 (1993), and in Stein, C., Lehrgerger, K., Yassouridis, A., Khoury, G.: Opioids as novel intraarticular agents in arthritis. In: Progress in Pain Research and Management, Fields, H. L., Liebeskind, J. C., eds., 1:289-296, IASP Press, Seattle (1994). A most important determination from these various studies is that the doses of the drugs required to produce analgesia in the peripheral tissues are extremely small and therefore devoid of the above mentioned side effects produced by dosages sufficient to operate on the brain.
In addition, it was determined that the endogenous ligands of peripheral opioid receptors (endorphins, the body's own pain killers) are located within the inflamed tissue. It was also determined that the endorphins can produce intrinsic analgesia within peripheral tissues both in animals and in humans (Stein (1993), ibid.). It was further noted that the peripheral opioid effects were more pronounced in inflamed than in non-inflamed tissues.
Severe pain caused or accompanied by inflammation in skin is a particularly intractable problem, because the underlying reasons for it tend to be both long-term and yet not inherently life-threatening, e.g., shingles and various kinds of burns, both of militate against the chronic systemic use of opioid agents. This led to initial investigations into whether it might be possible to be able to induce effective opioid analgesia in such cases without negative systemic opioid administration effects.
Initially, it was thought that it would be necessary to inject the morphine into an inflamed area since the inflammation activates the opioid receptors and it was also believed that the morphine had to be in an enclosed space to stay in contact with the area that was inflamed. The initial experiments were conducted in conjunction with arthroscopic surgery of the knee and a number of patients were medicated after arthroscopic surgery with injected morphine. These patients were medicated either with morphine alone, with a local anesthetic such as Marcaine or a combination of Marcaine and 1 mg of morphine. It was shown that patients receiving morphine into the joint had significantly more pain relief than patients receiving the same dose intravenously (demonstrating a local effect) and that this effect was mediated by intraarticular opioid receptors. Furthermore, patients who received just Marcaine after the surgery had relief but the relief typically did not extend beyond 12 hours or at most the next day after surgery. The patients who received Marcaine plus one mg of morphine in the knee had much better relief extending for at least twice as long as those that received Marcaine alone. See Stein et al. (1991).
At this point, it was still thought that it was necessary to keep the morphine in a closed space, such as in a knee, and the results of such controlled clinical studies reporting analgesia produced by morphine injected into the knee joint were reported in Stein et al., N. Engl. J. Med., 325: 1123-1126 (1991); Comment in N. Engl. J. Med., 325:1168-1169 (1991) and Khoury et al., Anesthes. 77:263-266 (1992). These studies have been replicated by several other groups throughout the world, but this application of morphine was relatively restricted to the practice of orthopedic surgeons using the morphine injected into a joint after arthroscopic surgery and further progress was restricted because it was thought that the morphine had to be contained in the closed space so as to keep the medication in close contact with the inflamed area.
Thus, there was a body of studies determining that opioid receptors were found in various peripheral tissues and suggesting that peripheral opioid effects would be more pronounced in inflamed than in non-inflamed tissues; however, there was no specific determination of how to provide an analgesic effect, using narcotics such as morphine, other than by injection of morphine into a closed space such as a joint. None of these reports discussed the possibility that pain relief could be topically induced in skin, whether inflamed or not, nor was it even known whether peripheral opioid receptors are present in human skin.
Nevertheless, while the need for adequate treatment and relief of pain in inflamed skin was evident, there was a lack of evidence that human skin contained peripheral opioid receptors, and there was doubt whether topical administration in the absence of the enclosed conditions akin to administration into the intra-articular space would work. Thus, the inventors of U.S. Pat. No. 5,589,480 conceived and developed a method of carrying out the concept of effecting topical local analgesia in inflamed skin with opioid agents.
The fact that the opioid effects are more pronounced in inflamed than in non-inflamed tissues is a considerable advantage considering that most painful conditions are associated with inflammation, for example, cancer, arthritis, trauma, post-operative pain, skin lesions, etc. The work disclosed in U.S. Pat. No. 5,589,480 demonstrated that extremely small systemically inactive doses of both conventional opioid drugs such as morphine, as well as other opioid agents, can produce potent analgesic effects after local application to inflamed skin in peripheral tissue. U.S. Pat. No. 5,589,480 discloses a method and preparation for a topical application of an opioid drug, such as morphine, for a direct activation of the peripheral opioid receptors on the surface of inflamed skin, without any substantial transdermal or transmucosal systemic delivery of the opioid.
Without wishing to be bound by theory, it is believed that the inflammatory process in peripheral tissue is associated with an increase in sensitivity to the antinociceptive effects of opioid agents, perhaps by activation of opioid receptors located on primary afferent neurons. This may occur by one or more means, e.g., de novo synthesis of opioid receptors which increases the number of receptors; axonal transport of pre-existing receptors to peripheral nerve terminals increasing their concentration and thus sensitivity; some other means of activation of pre-existing neuronal opioid receptors by the inflammatory process. See, e.g., Stein, C., Peripheral and non-neuronal opioid effects. Curr. Opin. Anaesth. 7:347-351 (1994). In addition, again without wishing to be bound by theory, inflamed skin is generally more permeable to topically-administered agents, because the inflammatory process destroys Schwann cells in the epidermis, leading to further exposure of the nerve terminals; inflammation also causes edema, which results in loss of integrity of the epidermis, making the nerve terminals more accessible to topical agents.
Although U.S. Pat. No. 5,589,480 demonstrated the effectiveness of topically-applied opioid analgesics without systemic delivery in inflamed skin, the treatment of peripheral pain in the case of non-inflamed skin faced the additional hurdles of lesser skin permeability, which thus required the addition of skin penetration enhancers and thus risked unwanted systemic delivery, and also did not have the same basis for expecting a successful outcome, i.e., that the inflammatory process in peripheral tissue is associated with an increase in sensitivity to the antinociceptive effects of opioid agents, e.g., due to an increase in the number and/or sensitivity of opioid receptors at peripheral nerve terminals induced by the inflammatory process. Therefore, it could not be predicted whether or how topical analgesia could be induced in non-inflamed skin or mucosa, at least without effecting systemic transdermal or transmucosal delivery as well. Moreover, it was desired to improve, if possible, the effectiveness of topical opioid analgesia induced in inflamed skin or mucosal tissue, without effecting systemic delivery of the opioid agents.
As expected, application of the pharmaceutical preparations in accordance with those disclosed in U.S. Pat. No. 5,589,480, which comprised, e.g., morphine sulfate in a simple pharmaceutically acceptable topical excipient, e.g., water, saline or hydrophilic gel such as KY Jelly, when applied to intact, non-inflamed skin in a patient suffering from non-inflammatory skin pain such as peripheral neuropathy, did not work. However, when skin-specific penetration enhancers are added to the topical formulation, it was found that even pain arising in non-inflamed skin could be successfully treated with topical, local analgesic agents which affect peripheral opioid receptors in the absence of delivery of clinically effective central nervous system levels. Moreover, these skin penetration enhancers were surprisingly shown to improve the effectiveness of local opioid analgesic agents which bind to opioid receptors in the treatment of pain in inflamed skin or mucosal tissue without the concomitant delivery of substantial amounts of the analgesic agent into the systemic circulation. This invention is fully disclosed in U.S. Ser. No. 09/028,117. The analgesic effect was thus potentiated by topically administering to a patient in need of such treatment a topically effective amount of an analgesic agent, which amount is systemically ineffective for induction of analgesia, admixed with a skin- or mucosa-specific penetration enhancer, such as, e.g., lecithin, and a pharmaceutically acceptable excipient for topical administration, preferably whereby effective analgesia in the non-inflamed skin or mucosal tissue is induced in the substantial absence of transdermal or transmucosal delivery of the opioid analgesic agent to the systemic circulation.
Peripheral Muscarinic Analgesia
L. C. Yang et al., Anesthesiology 88:334-339 (1998) discloses inducing post-operative analgesia by intra-articular administration of neostigmine in patients undergoing knee arthroscopy, using a counterpart of the method disclosed in Stein et al. (1991). Neostigmine is an acetylcholinesterase inhibitor; it was postulated to induce analgesia by a variety of pathways, presumably via induction of peripheral cholinerigic antinociception by elevating endogenous acetylcholine available to peripheral muscarinic receptors. Systemic administration of neostigmine through the spinal or epidural route of administration has been shown to have dose-related side effects similar to opioids, such as nausea, vomiting and pruritus.
It therefore was deemed desirable to provide an additional analgesic in the pharmaceutical arsenal of antinociceptives, by providing an effective topical method of treating pain via the muscarinic receptor pathway of analgesia, without the negative effects of systemic neostigmine administration. The work disclosed in U.S. application Ser. No. 09/083,431 demonstrated that small systemically inactive doses of neostigmine, can produce potent analgesic effects after local application to inflamed skin in peripheral tissue. Application Ser. No. 09/083,431 discloses a method and preparation for a topical application of a muscarinic drug, such as neostigmine, for a direct activation of the peripheral muscarinic receptors on the surface of inflamed skin, without any substantial transdermal or transmucosal systemic delivery.
Treatment of Acne with Opioid Analgesic Agents
U.S. Ser. No. 08/874,254 disclosed that topical application of small systemically inactive doses of opioid analgesic agents surprisingly were effective for the treatment of acne. However, especially in the case of minors suffering from acne, this treatment requires use of a controlled substance. Thus, it would also be desirable to provide an additional non-narcotic, non-teratogenic agent in the pharmaceutical arsenal of acne treatments, by providing another effective topical method of treating acne, e.g., via the muscarinic receptor pathway, without the negative effects of systemic neostigmine administration.